PID

The term "primary immunodeficiency diseases" (synonym: immunodeficiency syndromes) covers various diseases of the immune system that are characterized by a temporary or irreversible disturbance of the immune function. Congenital or primary immunodeficiencies (PID) are diseases in which the immunodeficiency is congenital, familial and/or inherited. The PID group is contrasted with diseases in which the immunodeficiency is acquired, which are referred to by the generic term "secondary immunodeficiencies". The best known example of this is AIDS (acquired immune deficiency syndrome).

In PID with phagocyte defects, both function may be impaired and the number of cells involved may be reduced. Congenital neutropenias, leukocyte adhesion defects (LAD), and PID with selective susceptibility to infection by mycobacteria(MSDM, mendelian susceptibility to mycobacterial disease) belong to this class of primary immunodeficiencies. Functional intracellular enzyme defects are exemplified in chronic granulomatosis(CGD) as a prototype for this group. In CGD, antibacterial reactive oxygen species cannot be produced because of an enzyme defect. The inadequate killing of phagocytized, i.e. intracellular, pathogens leads to invasive bacterial, (pyogenic) infections and mycoses.

Defects of neutrophil development, congenital neutropenia

• Elastase defect (Severe Congenital Neutropenia 1 = SCN1): autosomal dominant mutation in ELANE gene localized on chromosome 19p13.3 (ELANE stands for "Elastase, Neutrophil Expressed"). The mutated enzyme an elastase leads to defective folding of proteins, to increase apoptosis. Clinically, this leads to impaired myeloid differentiation. The risk for myelodysplasia/leukemia is increased. Manifestation as "severe congenital neutropenia/SCN" or cyclic neutropenia.
• GFI 1 defect (GFI 1 stands for "growth factor independent 1 transcription repressor") defect (SCN2): Autosomal dominant mutations in the GFI1 gene located on chromosome 1p22.1 result in impaired suppression of ELANE (ELANE stands for "Elastase, Neutrophil Expressed"). Clinically, the mutation leads to impaired myeloid differentiation as well as B/T cell lymphopenia.
• HAX1 defect (Kostmann syndrome, SCN3): autosomal recessive mutations in the HAX1 gene (HAX1 stands for HCLS1-Associated Protein X-1)on chromosome 1q21.3 result in inadequate control of neutrophil apoptosis. Clinically, this gene defect is associated with cognitive and neurological defects. Furthermore to impaired myeloid differentiation. Cave: the mutations are associated with increased risk of myelodysplasia/leukemia.
• G6PC3 defect (SCN4): autosomal recessive mutation in G6PC3 gene (G6PC3 stands for glucose-6-phosphatase catalytic subunit 3) which is localized on chromosome 17q21.31, leads to lack of glucose-6-phosphatase activity, aberrant glycosylation, increased neutrophil apoptosis. Decreased chemotaxis and O2 production. Further associated neutropenia as well as cardiac and urogenital malformations, venous ectasia of trunk and limbs, inner ear deafness.
• VPS45 defect (VPS45 stands for vacuolar protein sorting 45 homolog): Physiological protein regulates intracellular vesicle transport. Autosomal recessive mutations in the VPS45 gene (chromosome 1q21.2) lead to extramedullary hematopoiesis, myelofibrosis, nephromegaly.
• Glycogenosis type Ib: autosomal recessive mutation in G6PT1 gene (G6PT1 stands for "glucose-6-phosphate transporter 1") located on chromosome 17q21.31 lead to neutropenia, starvation hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly.
• WHAT GOF defect (X-linked neutropenia): X-linked recessive GOF mutation in the GTPase-binding WASP domain of the WASP gene (regulator of the actin cytoskeleton) results in loss of autoinhibition; monocytopenia and lymphoid abnormalities are possible.
• LAMTOR2 defect (LAMTOR=late endosomal/lysosomal adaptor, MAPK and MTOR activator 2): autosomal recessive mutations in LAMTOR2, the endosomal adaptor protein 14. The mutation leads to impaired endosomal biogenesis, partial albinism, short stature, hypogammaglobulinemia. CD8 cytotoxicity is decreased.
• Barth syndrome (3-methylglutaconic aciduria type II): X chromosomal recessive mutation in the tafazzin gene leads to abnormal lipid structure of the mitochondrial membrane, disturbance of carnitine metabolism; furthermore cardiomyopathy and myopathy, neutropenia, short stature.
• Cohen syndrome: autosomal recessive mutation in VPS13B gene leads to: retinopathy, developmental delay, deafness, obesity. Disorder of myeloid differentiation
• Clericuzio-type poikiloderma with neutropenia (PN): Genodermatosis with poikiloderma, usually noncyclic permanent neutropenia, recurrent sinopulmonary infections, pachyonychia, and palmo-plantar hyperkeratosis. The syndrome was first described in Navajo Indians by Clericuzio in 1991.
• JAGN1 (JAGN1 stands for "Jagunal Homolog 1) defect: autosomal recessive mutation in the JAGN1 gene, which regulates a secretory metabolic pathway leads to osteopenia and disruption of myeloid differentiation.
• 3-Methyl glutaconaciduria: autosomal recessive mutation in the CLPB gene leads to a deficiency in a mitochondrial protein as well as microcephaly, hypoglycemia, and complex neurological symptoms; furthermore, growth retardation, hypotonia, ataxia, convulsions, cataract, and disorder of myeloid differentiation.
• G-CSF receptor defect: autosomal recessive mutation in the CSF3R gene (CSF3R stands for Colony Stimulating Factor 3 Receptor) the G-CSF receptor leads to resistance to G-CSF therapy.
• SMARCD2 defect: autosomal recessive mutation in the SMARCD2 AR gene. The mutation leads to neutropenia, developmental defects, skeletal abnormalities and myelodysplasia.
• Specific granule defect: autosomal recessive mutation in the CEBPE gene , C/enhancer-binding protein ε; = myeloid transcription factor. The mutation results in neutrophils with bilobular nuclei, absence of secondary granules and defensins.
• Shwachman-Bodian-Diamond syndrome:autosomal recessive mutation in the SBDS gene. The mutation results in ribosomopathy/ AR /pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia.
• Shwachman-Diamond syndrome: autosomal recessive mutation in the DNAJC21 gene. The mutation leads to pancytopenia and exocrine pancreatic insufficiency.
• Shwachman-Diamond syndrome: autosomal recessive mutation in the EFL1 gene. The defect leads to pancytopenia and exocrine pancreatic insufficiency.
• HYOU1 defect: autosomal recessive mutation in the HYOU1 gene. The gene defect leads to hypoglycemia as well as inflammatory complications.

Motility disorders

• SRP54 defect: autosomal dominant mutation in the SRP54 gene. The gene defect leads to neutropenia as well as exocrine pancreatic insufficiency.
• Leukocyte adhesion deficiency syndrome (LAD1): autosomal recessive mutation in the ITGB2 gene(ITGB2 stands for "integrin subunit beta 2). Beta chain (CD18) of LFA-1, Mac 1. The mutation leads to delayed cord drop, chronic skin ulcers, non-purulent abscesses, periodontitis, leukocytosis, defective T + NK cell cytotoxicity.
• Leukocyte adhesion deficiency syndrome 2 (LAD2): autosomal recessiveMutation in the SLC35C1/FUCT1 gene leads to a deficiency in the GDP fucose transporter. The mutation leads to delayed wound healing, chronic ulcers of the skin, mental and physical retardation, leukocytosis; Bombay blood group (hh).
• Leukocyte adhesion deficiency syndrome 3 (LAD3): Mutation in the FERMT3/KINDLIN3 gene. The autosomal recessive mutation results in impaired Rap1 activation of ß1-3 integrins; clinically, there is delayed cord drop, chronic ulcers of the skin, periodontitis, leukocytosis, defective T + NK cell cytotoxicity, and bleeding tendency.
• Rac 2 defect(Rac 2 stands for ras-related C3 botulinum toxin substrate 2): the autosomal dominant LOF mutation of the GTPase RAC2 leads to a regulatory disorder of the actin skeleton. Adhesion, chemotaxis and O2- production are decreased. Furthermore delayed wound healing, leukocytosis.
• ß-actin defect: the autosomal dominantMutation in the ACTB gene (stands for "Actin, Cytoplasmic 1"), which codes for cytoplasmic actin. The mutation leads to mental retardation and short stature.
• Localized juvenile periodontitis: autosomal recessive mutation in the FPR1 gene (FPR1 stands for "formyl peptide and chemokine receptor"). The defective receptor function leads to peridontitis and impaired chemotaxis on FMLP (N-formyl-methionyl-leucyl-phenylalanine).
• Papillon-Lefèvre syndrome: autosomal recessive mutation in the CTSC gene (CTSC stands for cathepsin C). The mutation leads to a disorder of cathepsin activation of serine proteases. Clinical manifestations are diffuse transgressive palmoplantar keratosis, peridontitis, dental abnormalities and susceptibility to infection.
• WDR1 defect: autosomal recessive mutation in the WDR1 gene on chromosome 4p16.1 (WDR1 stands for "WD Repeat Domain 1"). Clinical manifestations are mild neutropenia, poor wound healing, severe stomatitis, "herniation" of neutrophil nuclei.
• Cystic fibrosis: autosomal recessive mutations in the CFTR gene on chromosome 7q31.2. (CFTR stands for "CF Transmembrane Conductance Regulator"). The mutation leads to the clinical picture of cystic fibrosis with respiratory infections, exocrine pancreatic insufficiency, increased chloride content in sweat.
• Neutropenia with combined ID due to MKL1 defect: autosomal recessive mutation in the MRTFA- gene (syn. MKL1) on chromosome 22q13.1-q13.2 (MRTFA- stands for Myocardin Related Transcription Factor A).
• Impaired expression of cytoskeletal genes. Clinically, this mutation leads to mild thrombocytopenia, defects in respiratory burst. Diseases associated with mutations in the MRTFA gene include "immunodeficiency 66" and "megakaryoblastic acute myeloid leukemia with (T1;22)(P13;Q13)".

Defects of the respiratory burst

• X-linked chronic granulomatosis : mutation in the CYBB gene (CYBB stands for "Cytochrome B-245 Beta Chain") which is located on chromosome Xp21.1-p11.4. The protein encoded by this gene is necessary for electron transport. Clinically, the mutation leads to recurrent bacterial and mycotic infections of various organs (lungs, skin, skin cells). Clinically, the mutation leads to recurrent bacterial and mycotic infections of various organs (lung, skin, especially Aspergillus!), granuloma formation and colitis with autoinflammation. Immunobiologically no O2 formation takes place, consequently no intracellular killing is possible. Note: Blood group: McLeod phenotype possible with large deletion.
• Autosomal recessive chronic granulomatosis (p22 phox defect): autosomal recessive mutation CYBA -gene (CYBA stands for "Cytochrome B-245 Alpha Chain") CYBA (Cytochrome B-245 Alpha Chain) is a protein coding gene located on chromosome 16q24.2. Diseases associated with CYBA include "chronic autosomal recessive granulomatous disease 4". Recurrent bacterial and fungal infections (especially Aspergillus!), granulomas and colitis in autoinflammation. Immunobiologically, there is no O2 formation, consequently no intracellular killing is possible.
• Autosomal recessive chronic granulomatosis (p47 phox defect): autosomal recessive mutation in the NCF1 gene (NCF1 stands for "Neutrophil Cytosolic Factor 1") which is located on chromosome 7q11.23 . The protein encoded by this gene is a 47 kDa cytosolic subunit of neutrophil NADPH oxidase. This oxidase is a "multicomponent enzyme" that is activated to produce superoxide anions. Mutations in this gene lead to recurrent bacterial and mycotic infections(especially Aspergillus!), granulomas and colitis in autoinflammation. Immunobiologically there is no O2 formation, consequently no intracellular killing is possible.
• Autosomal recessive chronic granulomatosis (p40 phox defect): autosomal recessive mutation in the NCF4 gene (NCF4 stands for "Neutrophil Cytosolic Factor 4") which is located on chromosome 22q12.3 . The protein encoded by this gene is a 40 kDa cytosolic subunit of neutrophil NADPH oxidase. This oxidase is a multicomponent enzyme that is activated to produce superoxide anions. Mutations in this gene lead to recurrent bacterial and mycotic infections(especially Aspergillus!), granulomas and colitis in autoinflammation. Immunobiologically there is no O2 formation, consequently no intracellular killing is possible.
• Autosomal recessive chronic granulomatosis: autosomal recessive mutation in the CYBC1 gene located on chromosome q24.3(?, differing data) (CYBA1 stands for "Cytochrome B-245 Alpha Chain1"). The mutation leads to recurrent infections, and an autoinflammatory phenotype.
• G6PD defect class 1: X chromosomal recessive mutation in the G6PD gene located on chromosome Xq28 (G6PD stands for "Glucose-6-Phosphate Dehydrogenase"). Glucose-6-phosphate dehydrogenase is a cytosolic enzyme whose main function is to produce NADPH, an important electron donor in oxidant defense and reductive biosynthetic reactions. G6PD deficiency can lead to neonatal jaundice, acute hemolysis, or severe chronic nonspherocytic hemolytic anemia. GeneCards summary for G6PD gene
• G6PD (glucose-6-phosphate dehydrogenase) is a protein-coding gene. Diseases associated with G6PD include nonspherocytic hemolytic anemia, due to G6PD deficiency (Anemia, Nonspherocytic Hemolytic, Due to G6pd Deficiency). G6PD deficiency confers resistance to malaria.

Other non-lymphocytic defects

• GATA2 (GATA binding protein 2): autosomal dominant mutation (MonoMAC) in the GATA2 gene on chromosome 3q21.3 (GATA2 stands for "Endothelial Transcription Factor GATA"). The mutaion in this gene leads to a loss of stem cells for monocytes, DC, NK and B cells. Clinically, there is susceptibility to mycobacterial infections, histoplasmosis, papillomavirus. Alveolar proteinosis. There is an increased incidence of MDS/AML/CMML.
• Pulmonary alveolar proteinosis in CSF2RB defect: autosomal recessive mutation in the CSF2RB gene located on chromosome 22q12.3. (CSF2RB stands for Colony Stimulating Factor 2 Receptor Subunit Beta). Thus impaired GM-CSF signal transduction. Pulmonary alveolar proteinosis. The growth factor GM-CSF has an essential role in surfactant metabolism in the alveoli. Reduced bioavailability of the cytokine GM-CSF leads to disruption of alveolar macrophage function and thus normal alveolar homeostasis.
• Pulmonary alveolar proteinosis in CSF2RA defect: Xchromosomal recessive mutation in the CSF2RA gene located on chromosome Xp22.32 (CSF2RA stands for Colony Stimulating Factor 2 Receptor Subunit Alpha). The mutation leads to impaired GM-CSF signal transduction (OMIM: 306250/OMIM: 425000). The growth factor GM-CSF has an essential role in surfactant metabolism in the alveoli. Reduced bioavailability of the cytokine GM-CSF leads to impaired alveolar macrophage function and thus normal alveolar homeostasis.